Functional Medicine

Schizophrenia starts in the gut

Schizo Title
This article is dedicated to all people with the diagnosis of schizophrenia who feel like they are stuck in a one-way street with the classical pharmacological treatment as a dead end. 
I can give you some hope as the pharmacological antipsychotic option is neither the only option, nor is it the most effective option. Many people made a full recovery from schizophrenia even without antipsychotic drugs. 

What we know about the human brain

We do not know much about how the human brain works. We really don’t. There are some attempts to -re-create the human brain. In the search for artificial intelligence progressive endevours like human brain emulation are trying to recreate the human brain from scratch and we are not even close to getting somewhere near the complexity of whats going on in our heads.
Miguel Nicolelis, a top neuroscientist at Duke University, says computers will never replicate the human brain :
“The brain is not computable and no engineering can reproduce it.”
We know very little about whats going on when the human brain goes haywire in circumstances like epilepsy. And we we know even less about chronic dysfunction of lesser magnitude as happens in depression, Parkinson’s, Alzheimers, autism or psychotic disorders. Yet people suffer from it on a broad scale. So we need to do something about it. But our solutions so far have been very far from perfect. 
Our first attempts had something to with just cutting the electric wiring to our fore brains as Walter Freeman did with his broad scale lobotomies. For obvious reasons this is not without severe side effects. So we stopped that as we discovered that the human brain is not simply a bundle of electric wiring, but is a highly biochemically active organ, almost like a gland. 
Thats why pharmacological psychotherapy is our current go-to approach. We use biochemistry that gets absorbed by the brain and does its magic right there in the brain. Well the brain uses biochemistry to create its functions, so we might be able to modulate this biochemistry to modulate its functions. Thats the idea of pharmacological psychotherapy. And it works. In some cases. And in some it does not. We still have a lot of side effects with our current pharmacological options. But we are able to control some of the debilitating symptoms of depression or psychosis. 
Nobel laureate, leading neurobiologist and clinical psychiatrist from Rockefeller University Prof. Dr. Paul Greengard said about the pharmacological options : “You have to understand, we as psychiatrists, we have no clue how the brain works. Our weapons, our machines, our treatments, they are so primitive because we do not remotely understand how the brain works.”
So what can we do when the pharmacological psychotherapy approach does not prove beneficial? Well we could make a little cognitive leap as we always did and think about the next level of interactions of the brain.
The brain is not on an island. It is in constant communication with the rest of our body, not only via electrical wiring, but to a large degree via biochemical transmitters. It secretes and receives neurotransmitters and hormones to and from all other organs. There is not only an electrical brain-body axis via our nervous system, but there is a myriad of biochemical axis like the brain-gonad axis (also know as hypothalamus, hypophysis, adrenal gonad axis), the brain-thyroid axis, the brain-gut axis, or even the brain-immune system axis. And thats only a fraction of the well-known biochemical pathways.
So maybe the next step in the treatment of psychiatric disorders could be to not look at it as an isolated brain dysfunction, but as a dysregulation of the whole organism. And thats what I want to try to do in this article.

What we know about schizophrenic disorders

The first thing to know is that schizophrenia is a disease with a wide variety of presentations. Not all patients with schizophrenia have the same symptoms. 
There are positive symptoms like hallucinations, mania or motor abnormalities. That doesn’t sound very positive. The word positive in this case refers to „more than usual“. It doesn’t mean „good“ as can be inferred when you take the word „positive“ too literal.
There are also „less than usual“ symptoms in the form of negative symptoms like depression, mood disorders, shallow emotional profile, social withdrawal and less emotion in speech and expression.
The third category of symptoms is referred to as „cognitive symptoms“ like memory loss, speech dysfunctions or inability to form abstract thought.
A schizophrenia is a wild mixture out of all three categories. Sometimes more on the „positive“ side. Sometimes more on the „negative“ and sometimes with a little „cognitive“ mixed in. That makes a clear diagnosis understandably difficult.
Schizophrenia also lacks a clear organic diagnostic criteria.
What I mean by organic diagnostic criteria is that a schizophrenic disorder cannot be pinpointed on an MRI like a brain tumour or cannot be seen in a blood sample like malaria. There is no single diagnostic test that will make you say : „Oh see, here we have the schizophrenia“. It is a clinical diagnosis from the constellation of symptoms and defined by the ICD-10/DSM-5 diagnostic criteria.

Conventional Treatment Options

The current treatment recommendations for schizophrenia are from 2005 and were originally considered to be valid until 2010. But since then no new guidelines have been published. The new guideline is supposed to be published at the end of 2017. 
There has been overwhelming literature that stated that it takes about 20 years for new research insights to make it into daily medical practice and that seems like a good example for that. 
The conventional treatment approach revolves around pharmacotherapy that targets the dopamine receptors of the brain. The dopamine system is like the amplifier of our brain. When they become down regulated, the whole organism becomes quiet, you turn them up, the whole organism becomes „louder“. A dopamine disease on the quiet side is Parkisons Disease. And we all know how quiet Muhammad Ali became. The „treatment“ for parksinsons is dopamine. And if you give a Parkinsons patient too much dopamine he becomes schizophrenic, because the dopamine receptors become over-activated. So the treatment for schizophrenia is to lower the volume on the dopamine receptors. By this, you lower the schizophrenic symptoms, but you also lower the overall volume of the human being.
The main medications are the newer antipsychotics olanzapine, risperidone, quetiapine, and ziprasidone. They work in some patients. Around 10-30% of patients get better with pharmacological treatment. But in most they do not. In fact many trials showed that these drugs are no better than placebo treatment.
Most patients stop using them because of their severe side effects and limited effectiveness. The CATIE clinical trial evaluated all medications. After 18 months, olanzapine was the „best“ drug, because „only“ 64% of patients stopped using it. 74% of patients stopped taking risperidone, 82% stopped using quetiapine, and 79% of patients stopped using ziprasidone. 
Especially risperidone, quetiapine and olanzapine have the side effect of severe weight management issues. People become fat. A great example is the freerunner Sebastien Charron. 


In 2010 he looked like this :
In 2016 after a couple of years of medication for schizophrenia this is him again :
He still has the moves, but he uncontrollably gained weight.
In combination with the pharmacological approach a psychotherapeutic intervention like Cognitive Behavioural Therapy (CBT) is recommended. Like all psychotherapeutic interventions these are highly dependant on the skillset and psychological make-up of the therapist. They can be highly successful or a waste of time. 

A Treatment Outlook 

There are some organic aberrations associated with schizophrenia. About fifty percent of patients have anatomical anomalies in the hippocampus, the amygdala or the temporal cortex. Local biochemical anomalies have been found in the dopamine system, the glutamate system or the NMDA receptor group. But so far no consistent biomarker for schizophrenic disorders has been identified.
We don’t even know if all schizophrenic patients that fit our diagnostic criteria of the ICD-10, all have the same disease. For all we know they might all have different diseases that present themselves with similar symptoms. This is no problem when we are all about diagnosing or naming something, but when we are all about treating we need more to hold on to.
So lets try to inch a little closer to being able to treat by looking at some of the things that are associated with schizophrenia. Because we might be looking not only as association, but even at causation. Going from association to causation is something every 3rd semester statistician would slap me for. But when there is an association combined with ample mechanistic evidence it is enough to consider an intervention. Just as there is an association and mechanistic evidence that parachutes will save your life when you jump out of an airplane. We don’t have to conduct a randomised controlled trial to evaluate whether parachutes prevent death when you jump out of an airplane. A schizophrenic with slim hopes that are narrowed down to the pharmacological pathway of psychotherapy might find these associations worth a consideration, just as everybody would grab a parachute before jumping out of an airplane.


There seems to be an inflammatory component to schizophrenia. Possibly even an autoimmune inflammation. What are the hints that this might be so?
Well for one, schizophrenic patients in general have a higher pro-inflammatory cytokine and C-reactive protein content in their blood and in their cerebrospinal fluid than non-schizophrenics. This clearly points to immune system activity, because inflammation is our immune systems tool of healing. It is like a farmer burning down his fields to stimulate new growth. But what if the fire doesn’t stop? There will be no new fields and plants growing if the fire keeps burning. And thats exactly what we see in schizophrenic brains after a longer period of time. They atrophy. Certain brain regions are so affected by the disease that they just „shrink“. We see a loss of central nervous system volume accompanied by an activation of microglia cells (the fire excavators of the brain), which points to an inflammatory atrophy.
We don’t know yet if this chronic inflammation is a reaction to the disease or the reason for the disease itself.
It might be part of the reason for the disease, because we see improvement in many patients who get an anti-inflammatory treatment.
Were the inflammation only a reaction to lets say a viral or bacterial infection, then the patients might get worse with anti-inflammatory or immune modulating treatment. But most of them don’t. 
Also, some of the negative symptoms of schizophrenia, like depression and social isolation can be induced even in healthy subjects in a short amount of time by injecting them with the same pro-inflammatory cytokines, which are found in many schizophrenic patients.
In a study at Imperial College London they looked at healthy subjects and only measured their immune activity in the brain and only from this tried to predict if they developed a schizophrenia. Two thirds of all the patients that this study identified as „ultra-high-risk“ did indeed develop a schizophrenia during the study. The plot thickens toward a large inflammatory role in schizophrenia.
The inflammatory process also explains a lot of the other biochemical findings that seem to dominate in a schizophrenic brain. A dysbalance in the kynurenic acid, the NMDA receptor system and the glutamatergic system is explained by an inhibition of the key enzyme in this construct, indoleamine-2,3-dioxygenase (IDO). This IDO enzyme is inhibited by a type 2 immune response, resulting in increased levels of kynurenic acid and the resultant glutamatergic dysbalance.
Takeaway from this can be that an indicator of an inflammatory contribution can be the activity of the IDO enzyme, which can be tested for in modern labs. If this enzyme activity is inhibited, the patient might benefit from an anti-inflammatory treatment.
Many types of anti-inflammatory treatments have been used. Most anti-psychotics have a subtle anti-inflammatory effect, which could explain some of their positive effects. Other classical pharmacological options include NSAIDs (e.g. Ibuprofen), Aspirin and COX-2 inhibitors. These drugs showed significant reduction of symptoms when used in the first couple of years of disease. They probably have to be used before the functional inflammatory process manifest themselves in permanent anatomical changes.
Also other anti-inflammatory substances like ACC or Omega-3 fatty acids showed significant improvements in placebo controlled double blind studies. 
Post-mortem analyses of schizophrenic patients revealed a very low omega-3 content of their brains compared to healthy controls. As Omega-3 fatty acids have a large involvement with healthy function of the brain on one hand and on the other hand contribute to a healthy regulation of the inflammatory cascade, it makes sense that omega-3’s lead to an improvement in schizophrenia. Four randomised controlled trials have shown positive benefits of Omega-3’s, but large meta-analyses so far could neither confirm nor deny the role of omega-3’s in the treatment of schizophrenia, which is why their are not part of widespread regular protocols.

Getting to the root of inflammation

Only treating the inflammation might get patients relief, but in my opinion this relief is rather diagnostic than therapeutic. If a patient responds positively to anti-inflammatory treatment the next step is to find out WHY the brain/body is inflamed. 
Reasons for brain inflammation can include : 
– viral infection
– bacterial infection
– parasitic/protozoic infections
– Fungal Infections
– Gut Disorders
– Heavy Metal Toxicity
– Mast Cell Dysfunction
– Autoimmune (Molecular Mimicry)
– Oxidative Stress
Like stated earlier, the inflammatory process is like a forest fire. It is meant to fight a threat or replace injured or even dying tissues with healthy and new tissues. Just stopping the inflammation takes away the heat, but doesn’t address the underlying problem in most cases. 

Viral/Bacterial Infections

When in 1957 in Helsinki a widespread epidemic of type A2 Influenza broke out no one suspected what would follow. Years later many people were admitted with schizophrenic symptoms. Scientists tracked back many of these patients to being born around the time of the epidemic. This virus-schizophrenia link has since been strengthened in hundreds of research papers on humans and has been replicated in the rodent model .
Influenza (H1N1), Herpes (HSV-1,HSV-2), Varicella (VZV), Epstein-Barr Virus (EBV), Rubella, and cytomegalovirus (CMV) are all associated with the onset of schizophrenic symptoms. In the treatment of schizophrenia it is of importance to find out if the onset of symptoms shows any temporal correlation with symptoms of viral infection. 
As the immune system of a mother is closely linked with its offspring it also important to know if the mother showed any signs of infection during or shortly before pregnancy. Even a placental insufficiency during pregnancy could point to a viral infection which goes unnoticed. In humans and in the rodent model a close link has been established between peri-natal infections of the mother and schizophrenic onset in the offspring, even later in adolescence. 
A viral component could open a treatment window for the success of antiviral therapy. Antibody serology to test for HSV-1, CMV, H1N1, EBV and CMV can point to a current or previous infection, but antibodies cannot always be found even if an infection is taking place. A decreased performance on a Wisconsin Card Sorting test has been found in schizophrenics who are indeed infected by HSV-1 compared to schizophrenics without a viral component, because the HSV-1 virus seems to attack the gray matter of the posterior cingulate gyrus in the brain, which is important for a good performance on this test.
Of the bacterial infections mostly the upper respiratory tract or gonococcal infections of the mother are associated with later onset of schizophrenia in her sons/daughters.
Takeaway : Consider peri-natal infections of the mother, temporally related infections of the patient, viral antibody serology and cognitive tests to identify a possible viral component of the disease.

Parasitic/Protozoic Infections

A published German case report from 1999 describes a schizophrenic patient, which showed signs of brain vessel inflammation in the MRI and schizophrenic symptoms. He showed no tick bite marks or any anamnestic events that lead to suspect Lyme disease (Borreliosis). But his antibody titer showed clear signs of infection and treatment for borreliosis relieved him of his symptoms. 
Again, this might be associated with the infection of the mother. The most robust epidemiological risk factor to developing a schizophrenic disorder later in life is being born in spring or in winter. This mirrors the seasonal distribution of Ixodes ticks   -which spread the Borrelia Burgdorferi parasite- nine month earlier during the time of conception.  
In the United States the regional areas for the highest risk of Lyme disease on one hand, and the highest risk for developing schizophrenia match almost perfectly.
As living in a crowded city is another epidemiological risk factor for developing a schizophrenic disorder this cannot be ignored as a confounding variable, though.
Another pointer to the potential role of tick-borne disease is that tetracyclic antibiotics have been proven effective in the treatment of schizophrenic disorders. The mechanisms are severalfold and range from glutamatergic modulation, and inhibiting microglial (remember the firefighters) activity. But tetracyclic antibiotics are also the go-to medication for borreliosis. 
Other infections to consider are syphilis (patient and mother), and toxoplasmosis (patient and mother).

Gut Disorders

A recent field of interest in medical research is the gut-brain axis. As around 85% of all serotonine is being produced in the gut, the gut is the largest immune organ, and accumulating evidence regarding gut disorders and mental dysfunctions, this is very worthwhile considering in every mental patient.
The historical Doctor Galen from the 2nd century before Christ already saw a close link between gut disorders and „insanity“ and prescribed his patients various diet and purging regimes. In modern medicine since the beginning of 20th century this idea is still alive, but we have identified many layers to gut disorders and their respective connections to „insanity“. 
Currently up to 90% of all patients with a diagnosis of Inflammatory Bowel Syndrome (IBS) have a psychiatric comorbidity.
There are many levels to gut disorders and they can broadly be categorised in :
1) Digestive Function 
2) Microbial Composition
3) Absorptive Function (Intestinal Permeability)
4) Immune Activity

Digestive Function and the brain 

The first level of digestive function includes the ability to break down food particles in the digestive tract and correctly mix the remaining indigestible materials with water for adequate stool production. Diarrhea, constipation, or indigested fats, carbs or proteins in the stool are a sign of a digestive malfunction, which can be the result of inadequate mastication (chewing), inadequate Hydrochloride (HCl) production of the stomach, gastric immobility or enzyme deficiencies (from gall bladder or pancreas). 
In 1907 Herter already identified an association between low stomach acid (HCl) and mental illness. The significance of this lies in the proteolytic ability (splitting protein particles) of HCl, which for one can split whole proteins into their respective amino acids including tryptophan, which is an important precursor to serotonine, which plays such a big role in mental disorders. On the other hand HCl controls the anaerobic microbial composition in the gut, especially in the small intestine. Too many anaerobic bacteria will increase the production of highly toxic substances in the gut, which may contribute to mental disease.
Another risk factor for this inadequate bacterial composition is limited gastric motility, which can be increased by taking antipsychotic, anti-dopaminergic, medications.

Gut Bacteria and Psychiatric Disorders

An inadequate bacterial composition or even the right bacteria in the wrong place (e.g. colon bacteria in the small intestine) can have very negative consequences on our immune system. They produce toxic by products which modulate our immune system in way that is highly correlated with psychiatric disorders.  On the other hand, the good bacteria produce beneficial by-products that protects us from inflammation and psychiatric disease. As indicated earlier, some such byproducts of aromatic amino acids tryptophan, alanine and tyrosine as well as short-chain fatty acids (SCFAs) include butyrate and propionate, produced in the gut during microbe fermentation processes.
Currently there exists no optimal standard to diagnose the microbial composition directly. But the good news is that the positive byproducts, especially butyrate and propionate can be measured in the stool.
Takeaway : Consider a stool analysis for microbial composition and microbial byproducts. Consider HCl and gastric motility analysis or a methane breath test to test for small intestinal bacterial overgrowth.

Intestinal Permeability and the Brain

This brings us to the third layer. After foods went through preliminary digestive process via mastication, enzyme splitting and microbial contribution, it is the question whether all necessary food particles like amino acids, and minerals are being absorbed correctly and exclusively. Correctly meaning the full absorption and exclusively meaning there are no other unnecessary particles being absorbed, which might trigger an immune response, when they reach the blood system.
  • A study on the diversity of the microbiome of the throat found that people with schizophrenia had 400 times the population of lactic acid bacteria than than their healthy counterparts. The same study found that some metabolic pathways for siderophores, glutamate, and vitamin B12 were also different in those with schizophrenia. They also found that the biodiversity of the microbiome was larger in the healthy controls.
  • Another study also found that the organism Lactobacillus phage phiadh was significantly more abundant in patients with schizophrenia. This microorganism has been tied to diabetes, which is common in people with schizophrenia. It was also found that none of those taking the drug valproate (Depakote) had Lactobacillus phage phiadh in their pharynx when tested, compared to the 17 of 35 individuals not taking the drug.
  • Some individuals with bipolar disorder and schizophrenia have consistent, low-grade inflammation associated with dysfunction in the gut microbiome.
  • Crohn’s Disease is associated with the yeast Saccharomyces cerevisiae. One study found that some people with schizophrenia and bipolar disorder have elevated levels of antibodies for this organism, especially those with gastric distress.
  • There is some evidence that some people with schizophrenia and bipolar disorder have sensitivities to lactose and gluten and that ingestion of these can lead to inflammation.
  • One study found that those hospitalized with acute mania had more recent exposure to antibiotics, suggesting an increased rate of bacterial infections in comparison with healthy controls.
Interestingly the gut barrier and the blood-brain barrier are structurally and functionally similar. This is why in schizophrenic patients there can be antibodies against food particles found in the cerebrospinal fluid, which can not be found in non-schizophrenic people.
Impairments of the gut lining with increased intestinal permeability are associated with all autoimmune disease currently known to medicine, as well as in or should I say including psychiatric disorders. 
Takeaway : Consider analysing intestinal permeability via lactulose/mannitol, Gliadin antibody, Zonulin and fecal A1AT.

Intestinal Immune Activity

When the immune system gets involved in a hyperpermeable gut things go bad really quick. This can not only manifest in the gut directly, but via molecular mimicry or blood-brain barrier dysfunctions can manifest directly in the brain. 
Food allergies and food sensitivities can play another role. While food allergies are an IgE mediated immune response to food, which can be felt easily most the time for the immediate and severe effects, the more subtle IgG mediated food sensitivities are not often evident to the patient, because they manifest themselves not immediately but rather in the days/weeks after consumption of the food, not like a wildfire, but rather like a slow cooking fire of the whole organism. 
The gold standard to identify an IgG mediated food sensitivity is an elimination diet, which reduces the diet to some basic non immune triggering foods and evaluate an improvement of symptoms. 
A case report by Bryan Kraft, published in „Nutrition & Metabolism“ in 2009 reports of 70 year old female who has been diagnosed with schizophrenia at the age of 17. After only 19 days of the elimination diet she was free of any symptoms. At a 12-months follow up, she modified her diet a little and was still free of any symptoms.
Takeaway : Consider a 6-week trial of an IgG specific elimination diet.